TLR4 was initially discovered as a receptor that recognizes lipopolysaccharide of gram negative bacteria and activates the innate immune system. However, in recent years, it has been clarified that it recognizes not only the innate immune response responsible for such infection defense but also various endogenous ligands produced in the aforementioned various diseases and activate various cells which play a central role in those diseases. In addition, it has been reported that expression of TLR4 is promoted in the lesions of various diseases, and development and progression of pathology in disease animal model such as TLR4 knockout mouse and mutant mouse are markedly suppressed. Therefore, TLR4 is suggested to play an important role in autoimmune disease and/or inflammatory diseases, or diseases such as cardiac diseases, renal diseases, hepatic diseases, central nervous system diseases, infectious diseases, malignant tumor, sepsis, and septic shock.
In addition to these diseases, the relationship with ischemia reperfusion injury (IRI) caused by resuming blood flow to an organ or tissue in an ischemic state, such as at the time of organ transplantation, has also been reported. High Mobility Group Box 1 (HMGB-1), which is one of the endogenous ligands of TLR4, increases in transplanted organs, and further, transplanted organs derived from donors having genetically hypofunctional TLR4 are resistant to dysfunction associated with IRI. Such known findings suggest that TLR4 signals caused by HMGB-1 play an important role in IRI (non-patent document 1, non-patent document 2).
From the above, a TLR4 signaling inhibitor (also referred to as “TLR4 inhibitor”) is expected to be a prophylactic or therapeutic drug for diseases such as autoimmune diseases and/or inflammatory diseases, or cardiac diseases, renal diseases, hepatic diseases, central nervous system diseases, infectious diseases, malignant tumor, sepsis, and septic shock.
Patent document 1 reports the following compound:
[wherein each symbol is as described in the document] as a TLR4 signaling inhibitor.
Patent document 2 reports the following compound:
[wherein each symbol is as described in the document] as a TLR4 signaling inhibitor.
Patent documents 3 and 4 report the following compound:
[wherein each symbol is as described in the documents] as a TLR4 signaling inhibitor.
In addition, the present Applicant reported as a TLR4 signaling inhibitor the following compound:
[wherein each symbol is as described in the document] in patent document 5, and the following compound:
[wherein each symbol is as described in the document] in patent document 6.